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Endothelial Cell E- and P-Selectin Up-Regulation in Murine Contact Sensitivity Is Prolonged by Distinct Mechanisms Occurring in Sequence¹

Olivier A. Harari^*, Julie F. McHale^*, Diane Marshall^*, Saifur Ahmed^*, Derek Brown, Philip W. Askenase^2,* and Dorian O. Haskard^3,*

^* British Heart Foundation Cardiovascular Medicine Unit, National Heart and Lung Institute, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom; and Celltech Ltd., Slough, United Kingdom 4 Abbreviations used in this paper: EC, endothelial cells; Pt, platelets; CS, contact sensitivity; ID, injected dose; i.d., intradermal; OX, 4-ethoxymethyl-2-phenyl-2-oxazolin-5-one (oxazolone).

The selectins are adhesion molecules that mediate the tethering and rolling of leukocytes on vascular endothelium. Although E-selectin and P-selectin are known to be expressed by endothelial cells (EC) in response to proinflammatory stimuli, their pattern and mechanisms of expression in immune-mediated inflammation remain poorly understood. By quantifying luminal endothelial selectin expression via i.v. administration of radiolabeled mAb, we detected constitutive expression of P-selectin, but not E-selectin, in mouse skin. Both selectins were transiently up-regulated after intradermal TNF-, IL-1, or IL-1ß. In contrast, during a contact sensitivity response to oxazolone, expression of both selectins was prolonged, with distinct peaks at 6 and 48 h. Experiments with P-selectin gene-targeted mice showed that the P-selectin measured was exclusively expressed by EC rather than platelets. The early and late phases of selectin expression in contact sensitivity were differentiated in terms of their requirement for prior sensitization, and the action of IL-1. Whereas the early phase was a nonspecific ’irritant’ response to oxazolone, the late phase was Ag specific and was partially IL-1 dependent. Therefore, persistence of both E- and P-selectin expression in vivo can occur as a result of sequential and distinct EC activation processes that appear to be at least partially different from those previously reported as stimulating ICAM-1 and VCAM-1 expression. The further elucidation of mechanisms of EC activation in this model may help determine the relative roles of selectins and ligands for leukocyte integrins in the sequential recruitment of T cells and other leukocyte subsets during ongoing immune-mediated inflammatory responses.